Clinical neuroscience
Contents
Neuronal development: Introduction lecture........................................................................................ 2
Leukodystrophies: Introduction lecture ............................................................................................... 12
Leukodystrophies: Disease mechanisms in VWM ................................................................................. 18
Leukodystrophies: Outcome measures ................................................................................................. 21
Leukodystrophies: What does water homeostasis have to do with it? ................................................. 24
Leukodystrophies: Current treatments ................................................................................................. 27
Leukodystrophies: Envision gene therapy ............................................................................................. 31
MS: Introduction lecture ...................................................................................................................... 34
MS: Etiological mechanisms and neuropathology ................................................................................ 39
MS: treatment ....................................................................................................................................... 42
MS: Exploring cognitive dysfunction ..................................................................................................... 44
MS: Imaging of cognitive decline........................................................................................................... 48
PD: Introduction lecture ....................................................................................................................... 54
PD: Brain imaging .................................................................................................................................. 59
PD: Disease mechanism towards a biological definition ....................................................................... 69
PD: Current therapy............................................................................................................................... 78
OCD: Introduction lecture .................................................................................................................... 82
OCD: From disease model to personalized targeting ............................................................................ 86
Depression: Introduction lecture ......................................................................................................... 89
Depression: Stress-related pathways .................................................................................................... 94
Neuro-oncology: Introduction lecture ................................................................................................. 98
,Neuronal development: Introduction lecture
Learning objectives
• Able to describe the landmarks in brain development
• Have knowledge of neurological disease resulting from a failure in the process
• Have basic knowledge about pediatric neurological development
Neural development refers to the processes that generate, shape, and reshape the nervous system,
from the earliest stages of embryogenesis to the final years of life. The study of neural development
aims to describe the cellular basis of brain development and to address the underlying mechanisms.
The field draws on both neuroscience and developmental biology to provide insight into the cellular
and molecular mechanisms by which complex nervous systems develop. Defects in neural
development can lead to cognitive and motor impairment, as well as neurological disorders such as
autism, Rett syndrome, and intellectual disability.
The human CNS follows a pattern of development. Building the human CNS requires the precise
orchestration and coordination of myriad molecular and cellular processes across a staggering array
of cell types and over a long period of time. Dysregulation of these processes affects the structure
and function of the CNS and can lead to neuro- logical or psychiatric disorders. Recent technological
advances and increased focus on human neurodevelopment have enabled a more comprehensive
characterization of the human CNS and its development in both health and disease. The aim of this
presentation is to highlight recent advancements in understanding of the molecular and cellular
landscapes of the developing human CNS, with focus on the cerebral neocortex, and the insights
these findings provide into human neural evolution, function, and dysfunction.
Figure: The figure provides a summary of some key cellular processes in the developing prefrontal cortex and functional
milestones. Illustrations in the top panel show the gross anatomical features of the developing and adult CNS, with prenatal
brain features magnified. The second panel, which is duplicated at the bottom of the figure, provides a timeline of human
development and the associated periods (designed by Kang et al., 2011), and age in postconceptional days (pcd), post-
conceptional weeks (pcw), and postnatal years (y). The schematic below details the approximate timing and sequence of key
cellular processes and developmental milestones. Bars indicate the peak developmental period in which each feature is
acquired; dotted lines indicate that feature acquisition occurs at these ages, though to a relatively minor degree; and arrows
indicate that the feature is present thereafter.
,Figure: An additional figure to figure 1, where different hallmarks are categorized by sensorimotor, communication, social-
emotional and cognitive.
Figure: Indicative of the biological challenge of precisely regulating diverse molecular and cellular processes over a
protracted period of time and across myriad cell types and regions, the CNS exhibits regionally and temporally distinct
patterns of vulnerability to various diseases and insults.
CNS development
Overview of Human CNS Development
• The human central nervous system (CNS) follows typical mammalian developmental patterns.
• Begins as a simple neural tube that separates from the embryonic ectoderm.
• Matures through complex, regulated molecular and cellular processes.
• Model organisms help researchers understand human neurodevelopmental processes.
Neurulation Process
• Neurulation: The process of forming the brain and spinal cord on the embryo's dorsal side.
• Nervous system originates from the ectoderm (outermost tissue layer).
• During the third week of development:
o The neuroectoderm appears, forming the neural plate along the embryo's dorsal
side.
o The neural plate is the source of most neurons and glial cells in the human CNS.
, o A groove forms in the neural plate.
• Fourth week of development:
o Neural plate wraps into a hollow neural tube.
o The neural tube later develops into the brain and spinal cord.
o Mutations in this stage can cause severe deformities (e.g., anencephaly) or
disabilities (e.g., spina bifida).
Gastrulation and Germ Layers
• Neurulation follows gastrulation, which organizes cells into three germ layers:
o Ectoderm: Surface layer; develops into skin and nervous system.
o Mesoderm: Middle layer; forms muscles, bones, and other organs.
o Endoderm: Innermost layer; develops into the gut and internal organs.
Formation of the Neural Plate and Tube
• After gastrulation, the notochord (a flexible rod from mesoderm) forms along the embryo's
back.
• In the third week of gestation:
o The notochord signals the ectoderm to transform into neuroectoderm.
o Neuroectoderm forms a strip of neuronal stem cells called the neural plate.
o The neural plate is the foundation of the CNS.
o The neural plate folds outward, forming a neural groove.
o In the neck region, neural folds of the groove close to form the neural tube.
▪ This process is called primary neurulation.
Structure of the Neural Tube
• Neural tube regions:
o Ventral (front) part: Basal plate.
o Dorsal (rear) part: Alar plate.
o The hollow interior of the neural tube is called the neural canal.
• By the end of the fourth week of gestation:
o Open ends of the neural tube, known as neuropores, close off.
Neuronal migration
• Neurons migrate each to their place of destination
• When they arrive at the right place, synaptogenesis causes the dendrites and axons to form.
Normal reflexes
• Motor asymmetry in newborns occurs when turning the head to one side causes the arm and
leg on that side to extend, while the opposite side flexes. This reflex helps develop muscle
coordination.
• Grabbing reflex
• Sucking reflex
• These primitive reflexes fade by around 6 months of age. When they reappear it’s usually a
sign of neurodegenerative disease.
Fourth Week Development
• Late fourth week:
